Derivatives of dioxan-2-alkyl carbamates, preparation thereof and application thereof in therapeutics

ABSTRACT

A compound corresponding to general formula (I): 
     
       
         
         
             
             
         
       
     
     in which R 1  represents a phenyl or naphthalenyl group optionally substituted with one or more halogen atoms or hydroxyl, cyano, nitro, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy, (C 3 -C 6 )cycloalkyl-O— or (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkoxy groups; R 2  represents either a group of general formula CHR 3 CONHR 4  in which R 3  represents a hydrogen atom or a methyl group and R 4  represents a hydrogen atom or a (C 1 -C 3 )alkyl, (C 3 -C 5 ) cycloalkyl or (pyridin-4-yl)methyl group; or a 2,2,2-trifluoroethyl group; or an (imidazol-2-yl)methyl group; or a (benzimidazol-2-yl)methyl group; or a phenyl group optionally substituted with one or more halogen atoms or cyano, nitro, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, trifluoromethyl or trifluoromethoxy groups; and n represents a number ranging from 1 to 3; in the form of a base, of an addition salt with an acid, of a hydrate or of a solvate. Also disclosed and claimed are the pharmaceutical compositions derived therefrom and their therapeutic use in treating a wide variety of diseases.

This application is a divisional of U.S. application Ser. No.12/510,326, filed Jul. 28, 2009, now allowed, which is a divisional ofU.S. application Ser. No. 11/426,964, filed Jun. 28, 2006, nowabandoned, which is a continuation of U.S. application Ser. No.11/062,541, filed Feb. 22, 2005, now U.S. Pat. No. 7,119,116 B2, issuedOct. 10, 2006, which is a continuation of International application No.PCT/FR2003/02,590, filed Aug. 27, 2003; all of which are incorporatedherein by reference in their entirety; which claims the benefit ofpriority of French Patent Application No. 02/10,707, filed Aug. 29,2002.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to 1,3-dioxan-2-ylalkylcarbamate derivatives, totheir preparation and to their use in therapeutics.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to general formula (I)

-   in which-   R₁ represents a phenyl or naphthalenyl group optionally substituted    with one or more halogen atoms or hydroxyl, cyano, nitro,    (C₁-C₃)alkyl, (C₁-C₃)alkoxy, trifluoromethyl, trifluoromethoxy,    benzyloxy, (C₃-C₆) cycloalkyl-O— or (C₃-C₆)cycloalkyl(C₁-C₃)alkoxy    groups;-   R₂ represents-   either a group of general formula CHR₃CONHR₄ in which R₃ represents    a hydrogen atom or a methyl group and R₄ represents a hydrogen atom    or a (C₁-C₃)alkyl, (C₃-C₅)cycloalkyl or (pyridin-4-yl)methyl group,-   or a 2,2,2-trifluoroethyl group,-   or an (imidazol-2-yl)methyl group,-   or a (benzimidazol-2-yl)methyl group,-   or a phenyl group optionally substituted with one or more halogen    atoms or cyano, nitro, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, trifluoromethyl    or trifluoromethoxy groups; and-   n represents a number ranging from 1 to 3.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of general formula (I) may comprise one or more asymmetriccarbons. They may exist in the form of enantiomers or ofdiastereoisomers. The compounds of general formula (I) may also exist inthe form of cis or trans stereoisomers. These enantiomers,diastereoisomers and stereoisomers, and also their mixtures, includingthe racemic mixtures, are part of the invention.

The compounds of formula (I) may exist in the form of bases or ofaddition salts with acids. Such addition salts are part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids which are of use, for example, forpurifying or isolating the compounds of formula (I) are also part of theinvention. The compounds of general formula (I) may be in the form ofhydrates or of solvates, namely in the form of associations or ofcombinations with one or more molecules of water or with a solvent. Suchhydrates and solvates are also part of the invention.

Compounds similar to those of the invention, for which R₂ represents alinear or branched (C₁-C₄)alkyl group, have been described asanticonvulsants in documents EP 0461958 and FR 2714056; both of whichare incorporated herein by reference in their entirety.

In the context of the invention:

-   the term “(C_(t)-C_(z)) where t and z can take the values of 1 to 6”    is intended to mean a carbon chain which can have from t to z carbon    atoms, for example “(C₁-C₃)” is intended to mean a carbon chain    which can have from 1 to 3 carbon atoms;-   the term “alkyl” is intended to mean a linear or branched, saturated    aliphatic group; for example a (C₁-C₃)alkyl group represents a    linear or branched carbon chain of 1 to 3 carbon atoms, more    particularly a methyl, ethyl, propyl or isopropyl;-   the term “cycloalkyl” is intended to mean a cyclic alkyl group; for    example, a (C₃-C₅)cycloalkyl group represents a cyclic carbon chain    of 3 to 5 carbon atoms, more particularly a cyclopropyl, cyclobutyl    or cyclopentyl;-   the term “alkoxy” is intended to mean an alkyloxy group containing a    linear or branched, saturated aliphatic chain;-   the term “halogen atom” is intended to mean a fluorine, a chlorine,    a bromine or an iodine.

Among the compounds of general formula (I), mention may be made ofpreferred compounds, which are defined as follows:

-   R₁ represents a naphthalenyl group optionally substituted with one    or more halogen atoms or hydroxyl, cyano, nitro, (C₁-C₃)alkyl,    (C₁-C₃)alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy,    (C₃-C₆)cycloalkyl-O— or (C₃-C₆)cycloalkyl(C₁-C₃)alkoxy groups;    and/or-   R₂ represents-   either a group of general formula CHR₃CONHR₄ in which R₃ represents    a hydrogen atom and R₄ represents a hydrogen atom or a (C₁-C₃)alkyl    group, preferably a methyl or an ethyl, or (pyridin-4-yl)methyl    group,-   or a 2,2,2-trifluoroethyl group,-   or a phenyl group optionally substituted with one or more halogen    atoms or cyano, nitro, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, trifluoromethyl    or trifluoromethoxy groups; and/or-   n represents 2 or 3.

The compounds for which both R₁, R₂ and n are as defined above areparticularly preferred.

By way of example of preferred compounds, mention may be made of thefollowing compounds:

-   2-amino-2-oxoethyl    trans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-(methylamino)-2-oxoethyl    trans-2-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate-   2-(methylamino)-2-oxoethyl    trans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2,2,2-trifluoroethyl    trans-2-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate-   2,2,2-trifluoroethyl    trans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   phenyl trans-2-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate-   phenyl trans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-amino-2-oxoethyl    trans-3-[5-(4-chloronaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-(methylamino)-2-oxoethyl    trans-3-[5-(4-chloro-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-(methylamino)-2-oxoethyl    trans-3-[5-(6-chloro-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-amino-2-oxoethyl    trans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-amino-2-oxoethyl    cis-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-(methylamino)-2-oxoethyl    trans-2-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate-   4-chlorophenyl    trans-2-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate-   2,2,2-trifluoroethyl    trans-2-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate-   2-(methylamino)-2-oxoethyl    trans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-(ethylamino)-2-oxoethyl    trans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-[(pyridin-4-yl)methylamino]-2-oxoethyl    trans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2,2,2-trifluoroethyl    trans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   phenyl    trans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-amino-2-oxoethyl    trans-3-[5-(6-cyclopropylmethoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   4-chlorophenyl    trans-3-[5-(6-cyclopropylmethoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2,2,2-trifluoroethyl    trans-3-[5-(6-cyclopropylmethoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-amino-2-oxoethyl    trans-3-[5-(6-phenylmethoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-amino-2-oxoethyl    trans-3-[5-(6-hydroxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-(methylamino)-2-oxoethyl    trans-3-[5-(6-hydroxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-amino-2-oxoethyl    trans-3-[5-(7-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-(methylamino)-2-oxoethyl    trans-3-[5-(7-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   2,2,2-trifluoroethyl    trans-3-[5-(7-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   phenyl    trans-3-[5-(7-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate-   phenyl trans-3-[5-(naphthalen-2-yl)-1,3-dioxan-2-yl]propylcarbamate-   2-(methylamino)-2-oxoethyl    trans-3-[5-(naphthalen-2-yl)-1,3-dioxan-2-yl]propylcarbamate-   2,2,2-trifluoroethyl    trans-3-[5-(naphthalen-2-yl)-1,3-dioxan-2-yl]propylcarbamate.

The compounds of the invention can be prepared according to variousmethods, illustrated by the following schemes.

Thus, a method of preparation (Scheme 1) consists in reacting an amineof general formula (II), in which R₁ and n are as defined in generalformula (I), with a carbonate of general formula (III), in which Urepresents a hydrogen atom or a nitro group and R₂ is as defined ingeneral formula (I), in a solvent such as toluene or dichloroethane, ata temperature of between 0 and 80° C.

The carbonates of general formula (III) can be prepared according to anymethod described in the literature, for example by reacting an alcoholof general formula HOR₂ with phenyl or 4-nitrophenyl chloroformate, inthe presence of a base such as triethylamine or diisopropylethylamine.

The compounds of general formula (I) for which R₂ represents moreparticularly an optionally substituted phenyl group (Ar) can be preparedby reacting an amine of general formula (II), as defined above, with anaryl chloroformate of general formula (IIIa) in a solvent such asdichloromethane or dichloroethane, in the presence of a base such astriethylamine or diisopropylethylamine, at a temperature of between 0°C. and the reflux temperature of the solvent.

According to Scheme 2, the compounds of general formula (I) for which R₂represents more particularly a group of general formula CHR₃CONHR₄ canbe prepared by reacting an amine of general formula (II), as definedabove, with carbon dioxide in the presence of a base such as cesiumcarbonate and a phase-transfer agent such as tetra-n-butylammoniumiodide, in a solvent such as N,N-dimethylformamide orN-methylpyrrolidone, and then with a haloacetamide of general formula(IV) in which V represents a chlorine, bromine or iodine atom and R₃ andR₄ are as defined in general formula (I).

A variant (Scheme 3) for obtaining the compounds of general formula (I)in which R₂ represents more particularly a group of general formulaCHR₃CONHR₄ consists in reacting an amine of general formula (II), asdefined above, with a carbonate of general formula (IIIb) in which Urepresents a hydrogen atom or a nitro group, R₃ is as defined in generalformula (I) and R₅ represents a methyl or ethyl group. The carbamateester of general formula (Ia) thus obtained is then converted to acompound of general formula (I), either by direct aminolysis by means ofan amine of general formula R₄NH₂ in which R₄ is as defined in generalformula (I), or by hydrolysis to an acid of general formula (Ia), inwhich R₅ represents a hydrogen atom, followed by coupling with an amineof general formula R₄NH₂ in which R₄ is as defined in general formula(I). The aminolysis reaction can be carried out in a solvent such asmethanol or a mixture of solvents such as methanol and tetrahydrofuran.The coupling reaction can be carried out according to any known methodfrom the literature, for example using isobutyl chloroformate in thepresence of a base such as diisopropylethylamine.

The carbonates of general formula (IIIb) can be prepared in a mannersimilar to the carbonates of formula (III).

Another variant (Scheme 4) for obtaining the compounds of generalformula (I) in which R₂ represents more particularly a group of generalformula CHR₃CONHR₄ consists in reacting a derivative of general formula(IIa), in which Z represents a hydroxyl, mesylate or tosylate group, ora chlorine, bromine or iodine atom, and R₁ and n are as defined ingeneral formula (I), with an oxazolidinedione of general structure (V)in which R₃ is as defined in general formula (I), to provide theoxazolidinedione derivative of general structure (VI). When Z representsa hydroxyl group, the reaction can be carried out according to theconditions of Mitsunobu (Synthesis, 1981, 1-28), for example by theaction of diethyl or diisopropyl azodicarboxylate in the presence oftriphenylphosphine. When Z represents a chlorine, bromine or iodineatom, or a mesylate or tosylate group, the reaction can be carried outin the presence of a base such as 1,1,3,3-tetramethylguanidine, sodiumhydride or sodium tert-butoxide in a solvent such as tetrahydrofuran,acetonitrile or dimethylformamide, at a temperature of between 0° C. andthe reflux temperature of the solvent. The oxazolidinedione derivativeof general formula (VI) thus obtained is then converted to a compound ofgeneral formula (I) by aminolysis by means of an amine of generalformula R₄NH₂ where R₄ is as defined in general formula (I).

The amines of general formula (II) can be prepared according to themethods of preparation described in patent applications EP 0461958, WO97/20836 and WO 98/55474, optionally adapted according to techniquesknown to those skilled in the art. All of the references describedherein are incorporated herein by reference in their entirety.

The compounds of general formulae (IIa), (IIIa), (IV) and (V), and alsothe amines R₄NH₂, when their method of preparation is not described, arecommercially available or described in the literature, or else can beprepared according to methods which are described therein or which areknown to those skilled in the art.

The compounds of general formula (Ia), in which R₁, R₃ and n are asdefined in general formula (I) and R₅ represents a hydrogen atom or amethyl or ethyl group, and the compounds of general formula (VI), inwhich R₁, R₃ and n are as defined in general formula (I), are novel andare also part of the invention. They are of use as syntheticintermediates for preparing the compounds of general formula (I).

The following examples illustrate the preparation of some compounds ofthe invention. These examples are not limiting and merely illustrate theinvention. The microanalyses, the IR and NMR spectra and/or the LC-MS(liquid chromatography coupled to mass spectroscopy) confirm thestructures and the purities of the compounds obtained.

The numbers indicated in brackets in the titles of the examplescorrespond to those of the 1st column of the table hereinafter.

Example 1 Compound No. 61 2-(Cyclopropylamino)-2-oxoethyltrans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate1.1. Ethyl [(phenoxycarbonyl)oxy]acetate

13.5 ml (105.6 mmol) of phenyl chloroformate are added, dropwise, atambient temperature to a solution of 10 g (96.15 mmol) of ethylglycolate and 27 ml (192.3 mmol) of triethylamine in 20 ml of tolueneand the mixture is stirred at ambient temperature for 2 h. The saltformed is separated and the filtrate is concentrated under reducedpressure to obtain 20 g of oily product, which are used withoutmodification in the following step.

1.2. Ethyltrans-[[[[3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propyl]amino]carbonyl]oxy]acetate

A solution of 10 g (33 mmol) oftrans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propanamine and8.9 g (39.8 mmol) of ethyl [(phenoxycarbonyl)oxy]-acetate, obtained instep 1.1, in 500 ml of toluene, is heated at 50° C. for 12 h. Themixture is allowed to return to ambient temperature, the insolublematerial is separated by filtration and the filtrate is concentratedunder reduced pressure. The residue is taken up with dichloromethane andwater, the aqueous phase is separated and extracted three times withdichloromethane, and the pooled organic phases are washed with asaturated aqueous sodium chloride solution and dried over sodiumsulfate. After evaporation of the solvent, the residue is purified bychromatography on silica gel, eluting with a 20/80 mixture of ethylacetate and cyclohexane. Finally, 7 g of pure product are obtained, inthe form of an oil which crystallizes:

Melting point: 74-76° C.

1.3.trans-[[[[3-[5-(6-Methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propyl]amino]carbonyl]oxy]aceticacid

40 ml of a 1N aqueous sodium hydroxide solution are added, dropwise, toa solution of 4 g (9.27 mmol) of ethyltrans-[[[[3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propyl]amino]-carbonyl]oxy]acetate,obtained in step 1.2, in 40 ml of dimethoxyethane, and the mixture isstirred at ambient temperature for 2 h. The mixture is concentratedunder reduced pressure, the residue is dissolved in a minimum of water,1N hydrochloric acid is added until a pH equal to 4 is obtained, theaqueous phase is extracted three times with dichloromethane, the organicphase is separated and dried over sodium sulfate, and concentration iscarried out at reduced pressure to obtain 3 g of acid.

Melting point: 114-116° C.

1.4. 2-(Cyclopropylamino)-2-oxoethyltrans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate

A solution of 0.169 g (1.24 mmol) of isobutylchloroformate in 5 ml oftetrahydrofuran is added, dropwise, under an inert atmosphere, to asolution of 0.5 g (1.24 mmol) oftrans-[[[[3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propyl]amino]-carbonyl]oxy]aceticacid, obtained in step 1.3, and 0.65 ml (3.70 mmol) ofN,N-diisopropylethylamine in 10 ml of tetrahydrofuran, cooled toapproximately −20° C., while at the same time maintaining thetemperature of the reaction medium below −15° C. Stirring is maintainedat this temperature for 1 h, then a solution of 0.078 g (1.36 mmol) ofcyclopropylamine in 5 ml of tetrahydrofuran is slowly added, and thestirring is continued at −15° C. for 1 h, and then at 20° C. for 10 h.Concentration is carried out under reduced pressure, the residue istaken up with ethyl acetate and water, the organic phase is separated,washed with a saturated aqueous sodium chloride solution and dried oversodium sulfate, concentration is carried out under reduced pressure, andthe solid is recrystallized from ethanol. Finally, 0.258 g of pureproduct is obtained.

Melting point: 176° C.

¹H NMR: (CDCl₃) δ (ppm) 8.10 (d, 1H); 7.65 (d, 1H); 7.35 (dd, 1H); 7.25(d, 1H); 7.15 (dd, 1H); 7.05 (d, 1H);

6.20 (broad m, 1H); 5.05 (broad m, 1H); 4.70 (t, 1H); 4.55 (s, 2H); 4.35(m, 2H); 3.95-3.90 (m, 6H); 3.30 (m, 2H); 2.75 (m, 1H); 1.75 (m, 4H);0.80 (m, 2H); 0.55 (m, 2H).

Example 2 Compound No. 49 2-Amino-2-oxoethyltrans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate

20 g (66 mmol) oftrans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propanamine, 64 g(198 mmol) of cesium carbonate and 73.14 g (198 mmol) oftetra-n-butylammonium iodide in suspension in 400 ml ofN,N-dimethylformamide are introduced into a 1 l three-neckedround-bottomed flask placed under an inert atmosphere. A stream ofcarbon dioxide is passed through the suspension, with vigorous stirring,for 2 h. 18.5 g (198 mmol) of chloroacetamide in solution in 70 ml ofN,N-dimethylformamide are then added dropwise, and the stream of carbondioxide is maintained for 5 h, and the stirring is continued at ambienttemperature overnight. The salts are separated by filtration, thefiltrate is concentrated under reduced pressure, the residue is taken upwith ethyl acetate and water, and the organic phase is separated andwashed with a 0.1N aqueous hydrochloric acid solution, then a saturatedaqueous sodium hydrogen carbonate solution and a saturated aqueoussodium chloride solution. The organic phase is dried over sodium sulfateand the filtrate is concentrated under reduced pressure, the residue ispurified by chromatography on silica gel, eluting with a 95/5 mixture ofethyl acetate and methanol, and the solid obtained is recrystallizedfrom ethyl acetate to obtain 6.5 g of pure product.

Melting point: 148-150° C.

¹H NMR: (DMSO) δ (ppm) 8.15 (d, 1H); 7.75 (d, 1H); 7.4 (dd, 1H); 7.35(d, 1H); 7.25 (m, 4H); 7.15 (broad m, 1H); 4.75 (t, 1H); 4.35 (s, 2H);4.25 (dd, 2H); 3.95 (dd, 2H); 3.90 (s+m, 4H); 3.05 (m, 2H); 1.60 (m,4H).

Example 3 Compound No. 3 2-(Methylamino)-2-oxoethyltrans-2-(5-phenyl-1,3-dioxan-2-yl)ethylcarbamate 3.1. Ethyltrans-[[[[2-(5-phenyl-1,3-dioxan-2-yl)ethyl]amino]carbonyl]oxy]acetate

The method of Example 1.2 is used. From 1 g (4.8 mmol) oftrans-2-(5-phenyl-1,3-dioxan-2-yl)ethanamine and 1.1 g (4.8 mmol) ofethyl [(phenoxycarbonyl)oxy]acetate, 0.740 g of ester is obtained, inthe form of an oil.

3.2. 2-(Methylamino)-2-oxoethyltrans-2-(5-phenyl-1,3-dioxan-2-yl)ethylcarbamate

3.3 ml (6.7 mmol) of a solution of methylamine (2M in tetrahydrofuran)are added, dropwise, to a solution of 0.70 g (2.1 mmol) of ethyltrans-[[[[2-(5-phenyl-1,3-dioxan-2-yl)ethyl]amino]-carbonyl]oxy]acetate,obtained in step 3.1, in 4 ml of methanol, and the mixture is stirred atambient temperature for 12 h. Concentration is carried out at reducedpressure, and the residue is purified by chromatography on silica gel,eluting with a 90/10 mixture of dichloromethane and methanol. The oilobtained is triturated in diisopropyl ether and 0.450 g of pure productis obtained.

Melting point: 89° C.

¹H NMR: (CDCl₃) δ (ppm) 7.35-7.20 (m, 3H); 7.15 (dd, 2H); 6.15 (broad m,1H); 5.45 (broad m, 1H); 4.75 (t, 1H); 4.60 (s, 2H); 4.20 (dd, 2H); 3.80(dd, 2H); 3.40 (m, 2H); 3.20 (m, 1H); 2.85 (d, 3H); 1.90 (m, 2H).

Example 4 Compound No. 63 1H-Imidazol-2-ylmethyltrans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate4.1. Phenyl (1-triphenylmethyl-1H-imidazol-2-yl)methylcarbonate

The procedure is carried out as described in Example 1.1. From 3 g (8.80mmol) of 1-triphenylmethyl-1H-imidazole-2-methanol (J. Het. Chem.,(1995), 32, 903-906) and 1.1 ml (8.80 mmol) of phenyl chloroformate, 3.9g of product are obtained, which is used unmodified in the followingstep.

4.2. (1-Triphenylmethyl-1H-imidazol-2-yl)methyltrans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate

The procedure is carried out as described in Example 1.2. From 2.5 g(8.28 mmol) oftrans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propanamine and3.8 g (8.28 mmol)of phenyl(1-triphenylmethyl-1H-imidazol-2-yl)methylcarbonate, obtained in step4.1, 3.2 g of a solid are obtained, in amorphous form.

4.3. 1H-Imidazol-2-ylmethyltrans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate

A solution of 0.6 ml (2.83 mmol) of trifluoroacetic acid in 2 ml ofdichloromethane is added, dropwise, at ambient temperature, to asolution of 1.9 g (2.83 mmol) of(1-triphenylmethyl-1H-imidazol-2-yl)methyltrans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate,obtained in step 4.2, in 150 ml of dichloromethane, and the mixture isstirred at ambient temperature for 12 h. Concentration is carried outunder reduced pressure, the residue is taken up with dichloromethane anda saturated aqueous sodium hydrogen carbonate solution, the organicphase is separated, washed with a saturated aqueous sodium chloridesolution and dried over sodium sulfate, concentration is carried outunder reduced pressure, and the residue is purified by chromatography onsilica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanoland aqueous ammonia. After recrystallization from ethyl acetate, 0.820 gof pure product is finally obtained.

Melting point: 130-132° C.

¹H NMR: (CDCl₃) δ (ppm) 10.0 (broad m, 1H); 8.10 (d, 1H); 7.65 (d, 1H);7.35 (dd, 1H); 7.25 (d, 1H); 7.15 (dd, 1H); 7.05 (dd, 1H); 7.00 (s, 2H);5.15 (m+s, 3H); 4.70 (t, 1H); 4.30 (m, 2H); 3.95-3.90 (m, 6H); 3.30 (m,2H); 1.85 (m, 4H).

Example 5 Compound No. 46 2-Amino-2-oxoethyltrans-3-[5-(4-chloronaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate5.1. trans-3-[5-(4-Chloronaphthalen-1-yl)-1,3-dioxan-2-yl]-1-propanol

0.75 ml (10 mmol) of 2,3-dihydrofuran and then 0.25 ml of a concentratedaqueous hydrochloric acid solution (37%) are added to a solution of 1.18g (5 mmol) of 2-(4-chloronaphthalen-1-yl)-1,3-propanediol in 10 ml ofdioxane. The mixture is allowed to react overnight at ambienttemperature and then 5 ml of water are added. The mixture is stirred for5 hours and is then diluted in 25 ml of water and 50 ml ofdichloromethane. The mixture is separated after settling out and theaqueous phase is extracted with 50 ml of dichloromethane. The organicphases are washed with 25 ml of a saturated aqueous sodium chloridesolution, drying is carried out over sodium sulfate and concentration iscarried out under reduced pressure. The residue is purified bychromatography on silica gel, eluting with a 70/30 and then 60/40mixture of cyclohexane and ethyl acetate. After recrystallization fromdiisopropyl ether, 0.557 g of product is obtained, in the form of whitecrystals.

Melting point: 127-129° C.

5.2. trans-3-[5-(4-Chloronaphthalen-1-yl)-1,3-dioxan-2-yl]propylmethanesulfonate

A solution of 0.256 g (2.23 mmol) of mesyl chloride in 2 ml ofdichloromethane is added, dropwise, to a solution of 0.530 g (1.72 mmol)of trans-3-[5-(4-chloronaphthalen-1-yl)-1,3-dioxan-2-yl]-1-propanolprepared in step 5.1 and of 0.48 ml (3.45 mmol) of triethylamine in 8 mlof dichloromethane cooled to 0° C. under an inert atmosphere. Thereaction mixture is stirred at 0° C. for 1 hour. 25 ml of water and 50ml of dichloromethane are added. The mixture is separated off aftersettling out and the aqueous phase is extracted with 50 ml ofdichloromethane. The organic phases are washed with 25 ml of a saturatedaqueous sodium chloride solution, drying is carried out over magnesiumsulfate and concentration is carried out under vacuum, to obtain 0.66 gof product in the form of a white solid used without modification in thefollowing step.

5.3.trans-3-[3-(5-(4-Chloronaphthalen-1-yl)-1,3-dioxan-2-yl)propyl]-1,3-oxazolidine-2,4-dione

A mixture of 0.660 g (1.71 mmol) oftrans-3-[5-(4-chloronaphthalen-1-yl)-1,3-dioxan-2-yl]propylmethanesulfonate, obtained in step 5.2, 0.208 g (2.05 mmol) of1,3-oxazolidine-2,4-dione (J. Med. Chem., 1991, 34, 1542-1543) and 0.396g (3.43 mmol) of 1,1,3,3-tetramethylguanidine in 10 ml oftetrahydrofuran is refluxed overnight under an inert atmosphere. Theresidue is taken up in 100 ml of ethyl acetate and 25 ml of water.Separation is carried out after settling out. The organic phase iswashed with 25 ml of water and then 25 ml of a saturated aqueous sodiumchloride solution. The aqueous phases are re-extracted with 50 ml ofethyl acetate. The organic phases are pooled, dried over sodium sulfateand concentrated under reduced pressure. The residue is purified bychromatography on silica gel, eluting with a 70/30 and then 60/40mixture of cyclohexane and ethyl acetate, to obtain 0.483 g of productin the form of a white solid.

Melting point: 125-127° C.

5.4. 2-Amino-2-oxoethyltrans-3-[5-(4-chloronaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate

0.470 g (1.20 mmol) oftrans-3-[3-(5-(4-chloronaphthalen-1-yl)-1,3-dioxan-2-yl)propyl]-1,3-oxazolidine-2,4-dione,obtained in step 5.3, is dissolved in 3.5 ml of tetrahydrofuran and 7 mlof a 7N solution of aqueous ammonia in methanol are added. The mixtureis allowed to react overnight at ambient temperature and is thenevaporated to dryness, and recrystallization is carried out from amixture of isopropanol and diisopropyl ether, to obtain 0.388 g ofproduct in the form of white crystals.

Melting point: 176-178° C.

LC-MS: M+H=407

¹H NMR (DMSO) δ (ppm): 8.35 (d, 1H); 8.25 (d, 1H); 7.8 (m, 3H); 7.4 (d,1H); 7.25 (m, 2H); 7.15 (s, 1H); 4.75 (t, 1H); 4.3 (s, 2H); 4.2 (m, 2H);4.0-3.9 (m, 3H); 3.05 (t, 2H); 1.65 (m, 2H); 1.6 (m, 2H).

Example 6 Compound No. 67 4-Chlorophenyltrans-3-[5-(6-cyclopropylmethoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate

0.205 g (0.60 mmol) oftrans-3-[5-(6-cylcopropylmethoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylamineis added, in small portions and at ambient temperature, to a solution of0.110 ml (0.78 mmol) of 4-chlorophenyl chloroformate and 0.205 ml (1.2mmol) of N,N-diisopropylethylamine in 6 ml of dichloromethane. Themixture is stirred at ambient temperature for 16 hours, then washing iscarried out with 5 ml of a saturated sodium bicarbonate solution. Thephases are separated and the organic phase is filtered through ahydrophobic sintered glass funnel. The filtrate is concentrated underreduced pressure and the residue is purified by chromatography on silicagel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate.After washing in 5 ml of diisopropyl ether, 0.176 g of a white solid isobtained.

LC-MS: M+H=496

Melting point: 159-162° C.

¹H NMR (CDCl₃) δ (ppm): 8.10 (d, 1H); 7.65 (d, 1H); 7.45-7.20 (m, 4H);7.20-7.00 (m, 4H); 5.30 (broad m, 1H); 4.75 (t, 1H); 4.35 (dd, 2H);4.10-3.80 (m, 5H); 3.50-3.25 (m, 2H); 1.95-1.70 (m, 4H); 1.45-1.20 (m,1H); 0.80-0.65 (m, 2H); 0.50-0.30 (m, 2H).

Example 7 Compound No. 68 2,2,2-Trifluoroethyltrans-3-[5-(6-cyclopropylmethoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate

0.075 ml (1.01 mmol) of 2,2,2-trifluoroethanol is added, dropwise and atambient temperature, to a suspension of 0.205 g (1.01 mmol) of4-nitrophenyl chloroformate and 0.555 g (2.02 mmol)N,N-diisopropylaminoethylpolystyrene (Ps-DIEA, 2% DVB, titre=3.66mmol/g) in 7.1 ml of dichloromethane. The mixture is stirred withorbital shaking and at ambient temperature for 16 hours. The resin isfiltered through a cartridge equipped with a sintered glass funnel andrinsing is carried out with 4 ml of dichloromethane. The filtrate isconcentrated under reduced pressure and the oily residue thus obtainedis taken up in 3.5 ml of 1,2-dichloroethane. 0.134 ml (0.78 mmol) ofN,N-diisopropylethylamine and 0.205 g (0.6 mmol) of3-[5-(6-cyclopropylmethoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylamineare successively added. This reaction mixture is heated at 60° C. for 16hours. After cooling, washing is carried out with 20 ml of a 1N sodiumhydroxide solution. The phases are separated and the organic phase isfiltered through a hydrophobic sintered glass funnel. The filtrate isconcentrated under reduced pressure and the residue is purified bychromatography on silica gel, eluting with an 80/20 mixture ofcyclohexane and ethyl acetate. After washing in 5 ml of diisopropylether, 0.076 g of white solid is obtained.

LC-MS: M+H=468

Melting point: 105-107° C.

¹H NMR: (CDCl₃) δ (ppm): 8.15 (d, 1H); 7.65 (d, 1H); 7.35 (dd, 1H); 7.25(m, 1H); 7.15 (d, 1H); 7.10 (d, 1H); 5.15 (broad m, 1H); 4.75 (t, 1H);4.50 (q, 2H); 4.30 (dd, 2H); 4.10-3.80 (m, 5H); 3.40-3.20 (m, 2H);1.90-1.65 (m, 4H); 1.45-1.20 (m, 1H); 0.75-0.60 (m, 2H); 0.50-0.35 (2H).

The following table illustrates the chemical structures and the physicalproperties of some compounds according to the invention. The compoundsin the table exhibit the trans relative configuration on the dioxanering, with the exception of compounds No. 37 and 50, which exhibit thecis relative configuration, and compounds No. 6, 9, 11, 13, 18, 20, 21and 43, which are in the form of a mixture of the cis and transstereoisomers. All the compounds in the table are in the form of bases.

TABLE (I)

M.p. No. R₁ n R₂ M + H (° C.)  1. phenyl 2 CH₂CONH₂ — 172-174  2. phenyl3 CH₂CONH₂ — 116-118  3. phenyl 2 CH₂CONHCH₃ —  89  4. phenyl 3CH₂CONHCH₃ — 116  5. phenyl 2 CH₂CF₃ 334 77-80  6. phenyl 3 CH₂CF₃ 34883-85  7. phenyl 2 phenyl 328 131-134  8. phenyl 3 phenyl 342 100-103 9. phenyl 2 2-chlorophenyl 362 95-98 10. phenyl 3 2-chlorophenyl 376129-131 11. phenyl 2 4-chlorophenyl 362 134-136 12. phenyl 34-chlorophenyl 376 117-121 13. phenyl 2 4-fluorophenyl 346 132-134 14.phenyl 3 4-fluorophenyl 360 106-109 15. phenyl 2 4-methylphenyl 342112-115 16. phenyl 3 4-methylphenyl 356 87-90 17. phenyl 22-methoxyphenyl 358 — 18. phenyl 3 2-methoxyphenyl 372 84-87 19. phenyl2 4-methoxyphenyl 358 130-132 20. phenyl 3 4-methoxyphenyl 372  99-10121. phenyl 2 3-trifluoro- 396 87-90 methylphenyl 22. phenyl 33-trifluoro- 410 128-131 methylphenyl 23. 4-fluorophenyl 14-chlorophenyl — 139-141 24. 4-fluorophenyl 2 CH₂CONHCH₃ — 124-126 25.4-fluorophenyl 3 CH₂CONHCH₃ — 150-152 26. 3-chlorophenyl 24-chlorophenyl — 123-125 27. 3-chlorophenyl 3 4-chlorophenyl — 89-91 28.4-chlorophenyl 1 4-chlorophenyl — 146-148 29. 4-chlorophenyl 1 CH₂CF₃ — 99-101 30. 2-methoxyphenyl 2 4-chlorophenyl — 144-146 31.3-methoxyphenyl 2 4-chlorophenyl — 116-118 32. 4-methoxyphenyl 34-chlorophenyl — 128-131 33. 3-trifluoro- 1 4-chlorophenyl — 116-119methylphenyl 34. 3-trifluoro- 1 CH₂CF₃ — 66-67 methylphenyl 35.3-trifluoro- 3 4-chlorophenyl — 93-96 methylphenyl 36. 3-trifluoro- 2CH₂CONHCH₃ — 118-120 methylphenyl 37. 3-trifluoro- 2 CH₂CONHCH₃ — 82-84methylphenyl 38. naphthalen-1-yl 3 CH₂CONH₂ — 112-114 39.naphthalen-1-yl 2 CH₂CONHCH₃ — 86-88 40. naphthalen-1-yl 3 CH₂CONHCH₃ —154 41. naphthalen-1-yl 2 CH₂CF₃ 384 111-113 42. naphthalen-1-yl 3CH₂CF₃ 398 89-92 43. naphthalen-1-yl 2 CH₂-benzimidazol- 432 — 2-yl 44.naphthalen-1-yl 2 phenyl 378 131-133 45. naphthalen-1-yl 3 phenyl 392125-127 46. 4-chloro- 3 CH₂CONH₂ 407 176-178 naphthalen-1-yl 47.4-chloro- 3 CH₂CONHCH₃ — 190-192 naphthalen-1-yl 48. 6-chloro- 3CH₂CONHCH₃ — 182-184 naphthalen-1-yl 49. 6-methoxy- 3 CH₂CONH₂ — 148-150naphthalen-1-yl 50. 6-methoxy- 3 CH₂CONH₂ — 144-147 naphthalen-1-yl 51.6-methoxy- 1 CH₂CONHCH₃ — 194-196 naphthalen-1-yl 52. 6-methoxy- 14-chlorophenyl — 133-136 naphthalen-1-yl 53. 6-methoxy- 1 CH₂CF₃ —142-144 naphthalen-1-yl 54. 6-methoxy- 2 CH₂CONHCH₃ — 136-138naphthalen-1-yl 55. 6-methoxy- 2 4-chlorophenyl — 129-131naphthalen-1-yl 56. 6-methoxy- 2 CH₂CF₃ — 93-95 naphthalen-1-yl 57.6-methoxy- 3 CH₂CONHCH₃ — 128-130 naphthalen-1-yl 58. 6-methoxy- 3CH₂CONHCH₂CH₃ — 170-172 naphthalen-1-yl 59. 6-methoxy- 3 CH(CH₃)CONHCH₃— 154 naphthalen-1-yl 60. 6-methoxy- 3 CH₂CONHCH₂- — 152 naphthalen-1-ylpyridin-4-yl 61. 6-methoxy- 3 CH₂CONH-cyclo- — 176 naphthalen-1-ylpropyl 62. 6-methoxy- 3 CH₂CF₃ — 111 naphthalen-1-yl 63. 6-methoxy- 3CH₂-imidazol-2-y1 — 130-132 naphthalen-1-yl 64. 6-methoxy- 3CH₂-benzimidazol- — 175-176 naphthalen-1-yl 2-yl 65. 6-methoxy- 3 phenyl— 128 naphthalen-1-yl 66. 6-cyclopropyl- 3 CH₂CONH₂ — 137-139methoxynaphthalen- 1-yl 67. 6-cyclopropyl- 3 4-chlorophenyl 496 159-162methoxynaphthalen- 1-yl 68. 6-cyclopropyl- 3 CH₂CF₃ 468 105-107methoxynaphthalen- 1-yl 69. 6-phenylmethoxy- 1 CH₂CONH₂ — 154-156naphthalen-1-yl 70. 6-hydroxy- 3 CH₂CONH₂ — 166-170 naphthalen-1-yl 71.6-hydroxy- 3 CH₂CONHCH₃ — 140-148 naphthalen-1-yl 72. 7-methoxy- 3CH₂CONH₂ — 156-158 naphthalen-1-yl 73. 7-methoxy- 3 CH₂CONHCH₃ — 144-146naphthalen-1-yl 74. 7-methoxy- 3 CH₂CF₃ 428 93-96 naphthalen-1-yl 75.7-methoxy- 3 phenyl 422 151-153 naphthalen-1-yl 76. naphthalen-2-yl 3phenyl 392 130-131 77. naphthalen-2-yl 3 CH₂CONHCH₃ — 144-146 78.naphthalen-2-yl 3 CH₂CF₃ 398 130-132

The compounds of the invention have been the subject of pharmacologicaltests to determine their inhibitory effect on the enzyme FAAH (FattyAcid Amido Hydrolase).

The inhibitory activity was demonstrated in a radioenzymatic assay basedon measuring the product of hydrolysis (ethanolamine [1-³H]) ofanandamide [ethanolamine 1-³H] by FAAH (Life Sciences (1995), 56,1999-2005 and Journal of Pharmacology and Experimented Therapeutics(1997), 283, 729-734). Thus, mouse brains (minus the cerebellum) areremoved and stored at −80° C. Membrane homogenates are preparedextemporaneously by homogenization of the tissues with a Polytron in a10 mM Tris-HCl buffer (pH 8.0) containing 150 mM NaCl and 1 mM EDTA. Theenzyme reaction is then carried out in 70 μl of buffer containing bovineserum albumin without fatty acids (1 mg/ml). The compounds tested, atvarious concentrations, the anandamide [ethanolamine 1-³H] (specificactivity of 15-20 Ci/mmol) diluted to 10 μM with non-radiolabeledanandamide and the membrane preparation (400 μg of frozen tissue perassay) are added successively. After 15 minutes at 25° C., the enzymereaction is stopped by adding 140 μl of chloroform/methanol (2:1). Themixture is stirred for 10 minutes and then centrifuged for 15 minutes at3 500 g. An aliquot (30 μl) of the aqueous phase containing theethanolamine [1-³H] is counted by liquid scintillation.

Under these conditions, the most active compounds of the inventionexhibit IC₅₀ values (concentration which inhibits by 50% the controlenzyme activity of FAAH) of between 0.005 and 1 μM.

It therefore appears that the compounds according to the invention havean inhibitory activity on the FAAH enzyme.

The in vivo activity of the compounds of the invention was evaluated ina test for analgesia. Thus, intraperitoneal (i.p.) administration of PBQ(phenylbenzoquinone, 2 mg/kg in a solution of 0.9% NaCl containing 5% ofethanol) to male OF1 mice weighing 25 to 30 g causes abdominal pulls, onaverage 30 twists or contractions during the 5 to 15 minute period afterinjection. The compounds tested are administered orally or i.p. insuspension in Tween 80 at 0.5%, 30 minutes, 60 minutes or 120 minutesbefore administration of PBQ. Under these conditions, the most potentcompounds of the invention reduce by 50 to 70% the number of pullsinduced by the PBQ, within a dose range of between 1 and 30 mg/kg.

The FAAH enzyme (Chemistry and Physics of Lipids, (2000), 108, 107-121)catalyzes the hydrolysis of endogenous derivatives of amides and ofesters of various fatty acids such as N-arachidonoylethanolamine(anandamide), N-palmitoylethanolamine, N-oleoylethanolamine, oleamide or2-arachidonoylglycerol. These derivatives exercise variouspharmacological activities by interacting, inter alia, with cannabinoidand vanilloid receptors. The compounds of the invention block thisdegradation pathway and increase the tissue level of these endogenoussubstances. They can be used in this respect in the prevention andtreatment of any pathological condition in which endogenous cannabinoidsand/or any other substrate metabolized by the FAAH enzyme are involved.

The following diseases and conditions may, for example, be mentioned:

pain, in particular acute or chronic pain of the neurogenic type:migraine, neuropathic pain including forms associated with the herpesvirus and with diabetes;

acute or chronic pain associated with inflammatory diseases: arthritis,rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis,Crohn's disease, irritable bowel syndrome;

acute or chronic peripheral pain;

dizziness, vomiting, nausea, in particular subsequent to chemotherapy;

eating disorders, in particular anorexia and cachexia of variousnatures;

neurological and psychiatric pathological conditions: shaking,dyskinesia, dystonia, spasticity, obsessive-compulsive behavior,Tourette's syndrome, all forms of depression and of anxiety of anynature and cause, mood disorders, psychoses;

acute or chronic neurodegenerative diseases: Parkinson's disease,Alzheimer's disease, senile dementia, Huntington's chorea, lesionsassociated with cerebral ischemia and with cranial and medullary trauma;

epilepsy;

sleep disorders including sleep apnea;

cardiovascular diseases, in particular hypertension, cardiacarrhythmias, arteriosclerosis, heart attack, cardiac ischemias;

renal ischemia;

cancers: benign skin tumors, papillomas and brain tumors, prostatetumors, brain tumors (glioblastomas, medulloepitheliomas,medulloblastomas, neuroblastomas, tumors of embryonic origin,astrocytomas, astroblastomas, ependyomas, oligodendroglyomas, plexustumor, neuroepitheliomas, epiphyseal tumor, ependymoblastomas, malignantmeningiomas, sarcomatosis, malignant melanomas, schwannomas);

disorders of the immune system, in particular autoimmune diseases:psoriasis, lupus erythematosus, diseases of the connective tissue orcollagen diseases, Sjögren's syndrome, ankylosing spondylarthritis,undifferentiated spondylarthritis, Behcet's disease, haemolyticautoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis,amyloses, transplant rejection, diseases affecting the plasmocytic line;allergic diseases: immediate or delayed hypersensitivity, allergicrhinitis or conjunctivitis, contact dermatitis;

parasitic, viral or bacterial infectious diseases:

AIDS: meningitis

inflammatory diseases, in particular diseases of the joints: arthritis,rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis,Crohn's disease, irritable bowel syndrome;

osteoporosis;

ocular conditions: ocular hypertension, glaucoma; pulmonary conditions:diseases of the respiratory tracts, bronchospasms, coughing, asthma,chronic bronchitis, chronic obstruction of the respiratory tracts,emphysema;

gastrointestinal diseases: irritable bowel syndrome, intestinalinflammatory disorders, ulcers, diarrhea, gastroesophageal reflux;

urinary incontinence and bladder inflammation.

The use of the compounds according to the invention, for preparing amedicinal product intended to prevent or treat the abovementionedpathological conditions, is an integral part of the invention.

A subject of the invention is also medicinal products which comprise acompound of formula (I), or a salt, or else a hydrate or a solvate,which is pharmaceutically acceptable, of the compound of formula (I).These medicinal products find their use in therapeutics, in particularin the prevention and treatment of the abovementioned pathologicalconditions.

According to another of its aspects, the present invention concernspharmaceutical compositions containing, as active principle, at leastone compound according to the invention. These pharmaceuticalcompositions contain an effective dose of a compound according to theinvention, or a salt, or a hydrate, or a solvate, which ispharmaceutically acceptable, of said compound and, optionally, one ormore pharmaceutically acceptable excipients.

Said excipients are chosen, depending on the pharmaceutical form and themethod of administration desired, from the usual excipients which areknown to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intrathecal, intranasal, transdermal, pulmonary, ocular or rectaladministration, the active principle of formula (I) above, or itsoptional salt, solvate or hydrate, can be administered in a single-doseadministration form, as a mixture with conventional pharmaceuticalexcipients, to animals and to humans, for preventing or treating theabovementioned disorders or diseases.

Suitable single-dose administration forms comprise oral forms such astablets, soft or hard gelatin capsules, powders, granules, chewing gumsand oral solutions or suspensions, forms for sublingual, buccal,intratracheal, intraocular and intranasal administration and foradministration by inhalation, forms for subcutaneous, intramuscular,intravenous or intrathecal administration and forms for rectal orvaginal administration. For topical application, the compounds accordingto the invention can be used in creams, ointments or lotions.

By way of example, a single-dose administration form for a compoundaccording to the invention in tablet form can comprise the followingcomponents:

compound according to the invention 50.0 mg mannitol 223.75 mg sodiumcroscaramellose 6.0 mg corn starch 15.0 mg hydroxypropylmethylcellulose2.25 mg magnesium stearate 3.0 mg

Said single-dose forms contain a dose so as to allow dailyadministration of 0.01 to 20 mg of active principle per kg of bodyweight, depending on the pharmaceutical form.

There may be particular cases in which higher or lower doses aresuitable; such doses also belong to the invention. According to usualpractice, the appropriate dose for each patient is determined by thephysician, depending on the method of administration, and the weight andresponse of said patient.

According to another of its aspects, the invention also concerns amethod for treating the pathological conditions indicated above, whichcomprises administering an effective dose of a compound according to theinvention, of one of its pharmaceutically acceptable salts, or of asolvate or of a hydrate of said compound.

1. A method of treating a disease in a patient comprising administeringto said patient a therapeutically effective amount of a compound offormula (I):

wherein R₁ represents a phenyl or naphthalenyl group optionallysubstituted with one or more halogen atoms or hydroxyl, cyano, nitro,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, trifluoromethyl, trifluoromethoxy,benzyloxy, (C₃-C₆)cycloalkyl-O— or (C₃-C₆)cycloalkyl(C₁-C₃)alkoxygroups; R₂ represents either a group of general formula CHR₃CONHR₄, or a2,2,2-trifluoroethyl group, or an (imidazol-2-yl)methyl group, or a(benzimidazol-2-yl)methyl group, or a phenyl group optionallysubstituted with one or more halogen atoms or cyano, nitro,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, trifluoromethyl or trifluoromethoxy groups;and wherein R₃ represents a hydrogen atom or a methyl group and R₄represents a hydrogen atom or a (C₁-C₃)alkyl, (C₃-C₅) cycloalkyl or(pyridin-4-yl)methyl group; n represents a number ranging from 1 to 3;or a pharmaceutically acceptable salt thereof, optionally in combinationwith one more pharmaceutically acceptable excipients, wherein saiddisease is selected from the group consisting of: acute or chronic pain,dizziness, vomiting, nausea, eating disorder, neurological orpsychiatric pathological condition, acute or chronic neurodegenerativedisease, epilepsy, sleep disorder, cardiovascular disease, renalischemia, cancer, disorders of the immune system, allergic disease,parasitic, viral or bacterial infectious disease, inflammatory disease,osteoporosis, ocular condition, pulmonary condition, gastrointestinaldisease or urinary incontinence.
 2. The method according to claim 1,wherein said disease is acute or chronic pain.
 3. The method accordingto claim 2, wherein said pain is of the neurogenic type.
 4. The methodaccording to claim 3, wherein said pain is selected from the groupconsisting of migraine and neuropathic pain including forms associatedwith the herpes virus and with diabetes.
 5. The method according toclaim 2, wherein said pain is selected from the group consisting ofarthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout,vasculitis, Crohn's disease, irritable bowel syndrome and acute orchronic peripheral pain.
 6. The method according to claim 1, whereinsaid disease is neurological or psychiatric pathological condition. 7.The method according to claim 6, wherein said neurological orpsychiatric pathological condition is selected from the group consistingof shaking, dyskinesia, dystonia, spasticity, obsessive-compulsivebehavior, Tourette's syndrome, depression, anxiety, mood disorder andpsychoses.
 8. The method according to claim 6, wherein said neurologicalor psychiatric pathological condition is obsessive-compulsive behavior.9. The method according to claim 6, wherein said neurological orpsychiatric pathological condition is Tourette's syndrome.
 10. Themethod according to claim 6, wherein said neurological or psychiatricpathological condition is depression.
 11. The method according to claim6, wherein said neurological and psychiatric pathological conditions isanxiety.
 12. The method according to claim 6, wherein said neurologicalor psychiatric pathological condition is mood disorder.
 13. The methodaccording to claim 6, wherein said neurological or psychiatricpathological condition is psychoses.
 14. The method according to claim1, wherein said disease is acute or chronic neurodegenerative disease.15. The method according to claim 14, wherein said acute or chronicneurodegenerative disease is selected from the group consisting ofParkinson's disease, Alzheimer's disease, senile dementia, Huntington'schorea, lesions associated with cerebral ischemia and with cranial andmedullary trauma.
 16. The method according to claim 1, wherein saidcompound is chosen from: 2-(methylamino)-2-oxoethyltrans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;2-amino-2-oxoethyltrans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;2-(methylamino)-2-oxoethyltrans-2-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate; and2-(methylamino)-2-oxoethyltrans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate; or apharmaceutically acceptable salt thereof.
 17. The method according toclaim 2, wherein said compound is chosen from:2-(methylamino)-2-oxoethyltrans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;2-amino-2-oxoethyltrans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;2-(methylamino)-2-oxoethyltrans-2-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate; and2-(methylamino)-2-oxoethyltrans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate; or apharmaceutically acceptable salt thereof.
 18. The method according toclaim 6, wherein said compound is chosen from:2-(methylamino)-2-oxoethyltrans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;2-amino-2-oxoethyltrans-3-[5-(6-methoxy-naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;2-(methylamino)-2-oxoethyltrans-2-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate; and2-(methylamino)-2-oxoethyltrans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate; or apharmaceutically acceptable salt thereof.